Kornfeld and Bach, U.S. Pat. No. 4,198,415 disclose and claim a group of trans-(.+-.)-5-permissibly-substituted-octahydro-1H(and 2H)-pyrazolo[3,4-g]quinolines of the formulas: ##STR2## wherein R is C.sub.1-3 straight-chain alkyl. The tautomeric mixture represented by Ia and Ib above can be prepared according to Kornfeld and Bach from a trans-(.+-.)-1-C.sub.1-3 straight-chain alkyl (or other substituent)-6-oxodecahydroquinoline (II) ##STR3## by reaction with dimethylformamide dimethylacetal or tris(dimethylamino)methane to give the corresponding 7-dimethylaminomethylene derivative which cyclizes with hydrazine to yield the desired trans-(.+-.)-5-substituted-4,4a,5,6,7,8,8a,9-octahydro 1H(and 2H)-pyrazolo[3,4-g]quinoline. The compounds thus prepared are active as dopamine D-2 agonists, useful in treating Parkinson's Syndrome or diseases characterized by an excess of circulating prolactin. The above chemistry is amplified in Bach et al, J. Med. Chem., 23, 481 (1980).
While the above chemistry has concerned the synthesis of a racemic or trans-(.+-.) tautomers, it should be apparent that the same procedures can be applied to the synthesis of the individual enantiomers, the 4aR,8aR and 4aS,8aS enantiomers. In this instance, one enantiomeric ketone, for example, the 4aR,8aR-1-substituted-6-oxodecahydroquinoline (IIa), is reacted with dimethylaminoformamide dimethylacetal and this derivative cyclized with hydrazine to yield the tautomeric pair, when R is n-propyl, 4aR,8aR-5-n-propyl-4,4a,5,6,7,8,8a,9-1H(and 2H)-octahydropyrazolo[3,4-g]quinoline (IIIa and IIIb). ##STR4##
This compound has recently been found by Hahn et al J.P.E.T., 224, 206 (1982)--see also the copending application of Hahn Ser. No. 438,833 filed Nov. 3, 1982, now U.S. Pat. No. 4,468,401, issued Aug. 28, 1984,--to be a potent antihypertensive agent. It has been given the generic name quinpirole and is currently on clinical trial in humans for the treatment of hypertension.
Quinpirole has also been found useful in the treatment of sexual dysfunction--see the copending application of Foreman, Ser. No. 518,906 filed Aug. 1, 1983. The other enantiomers, the 4aS,8aS compounds (IIIc and IIId) have been found to be dopamine D-1 agonists--see the copending application of Wong and Foreman, Ser. No. 575,126 filed Jan. 30, 1984. ##STR5##
The bicyclic ketone II is used as a starting material for the preparation of Ia and Ib. The racemate (II) is composed of two enantiomers, the 4aR,8aR and 4aS,8aS compounds (IIa and IIb). It should be noted at this point that, although the same 4aR,8aR nomenclature is used to describe the stereochemistry of both the 1-substituted-6-oxodeacahydroquinoline starting material and the 5-substituted-octahydro-1H(and 2H)-pyrazolo[3,4-g]quinoline final product, the 4a bridgehead carbon in the decahydroquinoline is the 8a carbon in the octahydro-1H(and 2H)-pyrazolo[3,4-g]quinoline final product and vice-versa. The racemic ketone (II) can be resolved into its respective enantiomers IIa and IIb by the method of Schaus and Booher, Ser. No. 439,107 filed Nov. 3, 1982, now copending. Application of the above masked formylation and hydrazine cyclization procedures to the resolved starting materials IIa or IIb yields the optically-active drugs, IIIa and IIIb or IIIc and IIId, respectively.
The racemic 1-substituted-6-oxodecahydroquinoline (II) was prepared by Kornfeld, Bach and coworkers (loc. cit.) by reacting a 4-acyloxycyclohexanone with pyrrolidine in the presence of acid to yield a pyrrolidine eneamine. Reaction of the eneamine with acrylamide gave a trans-(.+-.)-2-oxo-6-acyloxydecahydroquinoline. This derivative is then alkylated on the quinoline ring nitrogen with a C.sub.1-3 straight-chain alkyl (or allyl) halide in the presence of sodium hydride or the like base. This 1-alkyl or allyl derivative is next treated with LiAlH.sub.4 to reduce the 2-oxo group to a CH.sub.2 group and simultaneously remove, by reduction, the 6-acyl group, thus producing a 1-alkyl or allyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline. Reduction with sodium cyanoborohydride and acid yielded a trans-(.+-.)-1-alkyl or allyl-6-hydroxydecahydroquinoline. Oxidation of the secondary alcohol at C-6 with chromium oxide or the like yields the racemic starting material II.
Schaus, in his copending application, Ser. No. 821,863 filed Aug. 16, 1983, provides an alternate synthetic route to II. This route involves catalytic reduction of a quaternized 6-alkoxyquinoline (quaternized with a C.sub.1-3 straight-chain alkyl halide--an allyl halide cannot be used here because the allyl group would not survive the subsequent hydrogenation step). The product of this reaction, an 1-C.sub.1-3 straight-chain alkyl-6-alkoxy-1,2,3,4-tetrahydroquinoline is next subjected to a Birch reduction (Li in liquid ammonia) to give a mixture of 1-C.sub.1-3 straight-chain alkyl-6-alkoxy-1,2,3,4,5,8-hexahydroquinoline and 1-C.sub.1-3 straight-chain alkyl-6-alkoxy-1,2,3,4,4a,5-hexahydroquinoline. Reduction of the hexahydro dreivative with sodium cyanoborohydride or the like yields an octahydro compound having a trans-fused 4a,8a ring junction. Treatment of this compound with acid hydrolyzes the 6-enol ether to produce the desired trans-(.+-.)-1-C.sub.1-3 straight-chain alkyl-6-oxodecahydroquinoline (II).
Johnson et al, J.Org.Chem., 33, 3207 (1968) describe a group of enantiomeric 1-benzyl (or unsubstituted)-6-oxo or hydroxydecahydroquinolines. The oxygenation at C-6 was accomplished by a micro-organism, using decahydroquinoline or N-benzoyl decahydroquinoline as the substrate. The micro-organism hydroxylated the substrate at C-5, C-6, or C-7. Reduction of the benzoyl group to benzyl, hydrogenolysis of the benzyl group or oxidation of the hydroxyl to a ketone were steps carried out by standard chemical procedures on the mold metabolic products. Similar microbiological transformations were carried out using the separated enantiomers as substrates. The micro-organism was quite selective as regards which of the various stereoisomers it would oxygenate.
Momose and coworkers at Osaka University have published extensively on the hydrogenation of 7-hydroxyquinoline. In Paper I appearing in Chem.Pharm Bull., 25, 1436 (1977), all four stereoisomers of the transfused 7-hydroxydecahydroquinoline were isolated and characterized. Paper II, ibid, 1797, disclosed the synthesis of the cis-(.+-.)-7-oxodecahydroquinolines. One synthetic route involves the formation of a 2,7-dioxodecahydroquinoline in which the ketone group at C-7 was protected by ketal formation during LiAlH.sub.4 reduction at C-2. In none of these cis-(.+-.) derivatives was the ring nitrogen substituted. This omission was remedied in Paper III ibid, 26, 620(1976). This paper describes the isomerization of cis-(.+-.)-1-benzyl or benzoyl-2,7-dioxodecahydroquinolines to the corresponding trans configuration.
Neither trans-(.+-.)-1-C.sub.1-3 straight-chain alkyl or allyl-2,6-dioxodecahydroquinolines nor enantiomers thereof have been described.